Towards scalable and controlled synthesis of metal–organic framework materials using continuous flow reactors

Abstract

Metal–organic frameworks have emerged as one of the most diverse new families of materials in the past few years. Their hybrid structures, combinations of inorganic and organic moieties, give a wide range of complex architectures with resultant properties that are suitable for numerous important fields, including porosity for molecular sieving and sensing, heterogeneous catalysis, drug delivery, and energy storage. If applications of these materials are to be realised then scalable synthesis is required, taking laboratory batch reactions towards industrial production. Continuous flow reactors offer the most versatile method for scaling their solvothermal synthesis, with the largest range of materials accessible, in high yield, and with control over crystal form.

Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor

Abstract

Self-optimising flow reactors combine online analysis with evolutionary feedback algorithms to rapidly achieve optimum conditions. This technique has been applied to the final bond-forming step in the synthesis of AZD9291, an irreversible epidermal growth factor receptor kinase inhibitor developed by AstraZeneca. A four parameter optimisation of a telescoped amide coupling followed by an elimination reaction was achieved using at-line high performance liquid chromatography. Optimisations were initially carried out on a model compound (2,4-dimethoxyaniline) and the data used to track the formation of various impurities and ultimately propose a mechanism for their formation. Our protocol could then be applied to the optimisation of the 2-step telescoped reaction to synthesise AZD9291 in 89% yield.